Collagen is the body's major structural protein and is composed of three protein chains wound together in a tight triple helix. This unique structure gives collagen a greater tensile strength than steel. Approximately 33 percent of the protein in the body is collagen. Collagen, which occurs in several different forms, plays a key role in providing the structural scaffolding surrounding cells that helps to support cell shape and differentiation, similar to how steel rods reinforce a concrete block. Collagen 1, which is the most prevalent form, provides the supportive framework for the skin.
Collagen is secreted by fibroblasts, which are specialized skin cells located in the dermis. In order to signal or turn on the production of skin structural proteins, fibroblast cells have specially shaped receptors on their outside membranes that act as binding sites to which signal molecules with a matching shape can fit. When the receptors are bound by the correct combination of signal molecules (called fibroblast growth factors, or FGFs), the fibroblast begins the production of collagen. This occurs initially through the production of procollagen, a water soluble pre-eursor, within the fibroblast cells and subsequently through the assembly of procollagen threads into insoluble collagen fibers within the extracellular matrix.
Fibroblasts also produce other skin structural proteins such as elastin (a protein which gives the skin its ability to snap back) and glucosaminoglycans (GAGs). GAGs make up the ground substance that keeps the dermis hydrated. Hyaluronic acid is an example of a GAG. Hyaluronic acid is a polysaccharide that is responsible for lubricating and moisturizing many of the body's cells. Over 50% of the body's hyaluronic acid is present within the skin. Hyaluronic acid can bind up to 1000 times its weight in water and thus keeps moisture within skin's extracellular matrix, the fluid-filled space between cells, maintaining the youthful appearance of skin.
Collagen and GAGs, such as hyaluronic acid, work in concert to give skin its strength, durability, and smooth, plump appearance. The body's ability to regenerate collagen and hyaluronic acid is affected over time by intrinsic and extrinsic factors that include normal aging, disease, and environmental factors. The most common causes of this are UV radiation (photoaged skin) and age (chronologically aged skin) although factors such as smoking, poor nutrition, chronic stress, certain medications (non-steroidal anti-inflammatory drugs, hormonal treatments, chemotherapy, etc.), and diseases, particularly autoimmune conditions that target collagen, also impair the body's ability to produce and maintain the necessary levels of collagen and hyaluronic acid.
The common phenotypic signs of photoaged skin include wrinkles, roughness, mottled pigmentation, changes in epidermal thickness, skin sagging and reduced ability to regenerate. A number of growth factors and cytokines, such as EGF, IL1 and TNF-α, are induced in skin cells as a result of UV damage. These UV induced factors trigger a signal transduction cascade that ultimately leads to an increase in expression of transcription factor AP-1. The result of the enhanced expression and activity of AP-1 is increased expression of matrix metalloproteinases (MMPs), decreased procollagen synthesis and biochemical changes in extracellular matrix and epidermis that progress with age and define the aged-skin phenotype. Fisher G J, Kang S, Varani J, Bata-Csorgo Z, Wan Y, Datta S, Voorhees J J (2002). Mechanisms of photoaging and chronological skin aging. Arch Dermatol 138: 1462-1470. Expression of proinflammatory genes and molecules, such as COX-2 and prostaglandin, have also been found to result from UV-B radiation exposure, Nichols J A, Katiyar S K (2010), Skin photoprotection by natural polyphenols: anti-inflammatory, antioxidant and DNA repair mechanisms. Arch Dermatol Res 302: 71-83, and are associated with cellular senescence Kuilman T, Peeper D S (2009). Senescence-messaging secretome: SMS-ing cellular stress. Nature reviews Cancer 9: 81-94, and Heng M C (2010). Curcumin targeted signaling pathways: basis for anti-photoaging and anti-carcinogenic therapy. Int J Dermatol 2010. 49: 608-622. Hence controlling inflammation in photo aging is of interest for skin anti-aging regimen.
In contrast to UV induced photo aging, chronological aging of the skin is a natural process that occurs gradually over the lifetime of an individual. Photo protected aged skin, which develops less mottled pigmentation with finer lines, is generally thinner and more lax than photo-aged skin, Accumulation of molecular damage (including DNA) caused by an increase in reactive oxygen species (ROS) is common to both photo- and non-photo skin aging process. Like photo aging chronological aging is thought to strongly involve the accumulation of damage caused by an increase ROS induced by mitochondrial oxidative metabolism, Camougrand, N. and M. Rigoulet (2001), Aging and oxidative stress: studies of some genes involved both in aging and in response to oxidative stress. Respir Physiol 128: 393-401.
The stimulation of collagen and hyaluronic acid production may reverse some of the damage caused by UV rays and the passage of time, and thus the discovery of natural or synthetic compounds that are safe and effective in reversing and or halting the skin aging or photoaging is of great interest to consumers. The present invention thus provides new compositions and methods for stimulating collagen and hyaluronic acid production. It is a further object of the invention to improve the overall appearance of skin, including reversing, and/or preventing signs of aging, such as skin wrinkles, by stimulating collagen and hyaluronic acid production with cosmetic compositions comprising effective amounts of N-heteroarylbisamide analogs. A further object of the invention is to prevent, and or ameliorate various conditions of the skin resulting from disruption of collagen or hyaluronic acid homeostasis, i.e. increased degradation with insufficient production thereof or vice versa, through the administration of a dermatologically effective amount of a N-heteroarylbisamide analog to a subject in need thereof.
The foregoing discussion is presented solely to provide a better understanding of the nature of the problems confronting the art and should not be construed in any way as an admission as to prior art nor should the citation of any reference herein be construed as an admission that such reference constitutes “prior art” to the instant application.